Hydroxychloroquine Requires Ophthalmologic Monitoring Because Retinopathy is Irreversible and Can Progress Even After Drug Discontinuation
Hydroxychloroquine causes dose-dependent retinal toxicity that permanently damages photoreceptors and the retinal pigment epithelium, with no available treatment once damage occurs—making early detection through regular ophthalmologic screening essential to prevent central vision loss. 1
Why the Retinopathy is So Dangerous
The retinopathy is not reversible, and there is no present therapy. 1 The key pathophysiologic concern is that:
Primary damage occurs to photoreceptors, followed by secondary disruption of the retinal pigment epithelium (RPE). 1 This creates a cascade of irreversible cellular degeneration.
Toxicity can progress for years after stopping the medication, even when recognized early. 1 The amount of progression correlates with severity at detection—advanced cases show widespread RPE and retinal atrophy with loss of visual acuity, peripheral vision, and night vision. 1
When retinopathy is not recognized until a bull's-eye maculopathy appears, the disease can progress for years with foveal thinning and eventual loss of visual acuity. 1 This classic "textbook" pattern represents advanced disease that should no longer occur with proper screening. 1
The Critical Window for Prevention
Central vision can be preserved if damage is recognized before there are changes in the RPE—specifically, before any RPE loss occurs. 1 This is why screening focuses on detecting early photoreceptor damage:
When retinopathy is recognized early (before RPE damage), there is only mild and limited progression after discontinuing the medication, and the fovea is preserved. 1
Damage detected at an early stage can stabilize without serious visual loss if hydroxychloroquine is discontinued, with minimal foveal thinning of approximately 4 μm/year. 2
Modern screening should detect retinopathy before it is visible in the fundus. 1 The goal is to identify focal interruption of the ellipsoid zone and localized parafoveal thinning of photoreceptor layers on spectral-domain OCT. 2
Risk Factors That Necessitate Monitoring
The overall prevalence of hydroxychloroquine retinopathy is 7.5%, but this varies dramatically with dosage and duration. 3 Specific risk thresholds include:
Daily consumption >5.0 mg/kg real body weight increases risk 5.67-fold (95% CI, 4.14-7.79). 3
Duration >10 years increases risk 3.22-fold (95% CI, 2.20-4.70). 3 For daily consumption of 4.0-5.0 mg/kg, prevalence remains <2% within the first 10 years but rises to almost 20% after 20 years. 3
Renal disease increases risk 2.08-fold (95% CI, 1.44-3.01) because reduced renal function increases systemic HCQ levels. 1, 3
Concurrent tamoxifen use increases risk 4.59-fold (95% CI, 2.05-10.27). 1, 3
The Screening Algorithm
Baseline Examination
A baseline retinal examination should be performed within the first few months of HCQ usage to rule out underlying retinal disease. 1 This establishes a reference point and identifies pre-existing conditions (significant macular degeneration, severe diabetic retinopathy, hereditary retinal disorders) that might complicate recognition of toxicity. 1
Annual Screening Timeline
If there are no special risk factors (high daily dose, kidney disease, concurrent tamoxifen), screening for retinopathy after baseline may be deferred for 5 years, but thereafter should be performed annually. 1
Screening should begin sooner if major risk factors are present. 1 Check dosage relative to weight at every visit. 1
Required Testing Modalities
The mainstays of early detection are spectral-domain OCT (objective) and automated visual fields (subjective). 1 Specifically:
Screening should start with OCT, as anatomic changes are more specific for detecting toxicity than subjective visual field testing. 1, 2
Look for localized parafoveal thinning of photoreceptor layers and focal interruption of the ellipsoid zone on spectral-domain OCT—these are the most specific early anatomic markers. 2
Visual fields should typically focus on the central 10 degrees of the retina (10-2 protocols) for non-Asian patients. 1 Fields should not be considered definitive until repeat testing shows a consistent partial or full ring scotoma. 1
Racial Considerations in Screening
Most patients of European descent show initial photoreceptor damage in the classic parafoveal distribution, while most patients of Asian descent show initial damage in a more peripheral extramacular distribution near the arcades. 1
For East Asian patients, screening should preferably include broader OCT (30° line scans) and/or wider field tests (24-2 or 30-2). 1, 2 Standard central 10-degree protocols may miss toxicity in this population. 2
Critical Pitfalls to Avoid
Fundus examination and ophthalmoscopy detect only late-stage disease and should not be used for screening. 2 Normal visual acuity is maintained until severe stages, so it cannot be used to rule out toxicity. 2
Time-domain OCT lacks sufficient resolution to detect early toxic changes and should not be used for screening. 2
HCQ is an important drug for control of many rheumatic diseases and should not be discontinued without adequate cause. 1 The earliest changes on OCT and visual fields can be subtle—questionable findings should be repeated or validated with additional procedures to avoid unnecessary cessation of valuable medication. 1
The decision to discontinue HCQ should be reached through shared decision-making involving the patient, prescribing physician, and eye care provider, considering the severity of the rheumatic disease and estimated risk of visual loss if the drug is continued. 1
Patient and Prescriber Counseling
Patients and prescribing physicians should be informed about risk of toxicity, proper dose levels, and the importance of regular annual screening. 1 The FDA label specifically instructs patients to seek medical attention promptly if they experience decreased vision or decreased dark adaptation. 4
Ophthalmologists provide a valuable service not only by screening but also by advising medical colleagues and patients about risk, safe dosing, and appropriate screening procedures. 1